Phosphatidylinositol 3-kinases (PI3Ks) comprise a family of lipid kinases that catalyze the transfer of phosphate to the D-3′ position of inositol lipids to produce phosphoinositol-3-phosphate (PIP), phosphoinositol-3,4-diphosphate (PIP2) and phosphoinositol-3,4,5-triphosphate (PIP3) that, in turn, act as second messengers in signaling cascades by docking proteins containing pleckstrin-homology, FYVE, Phox and other phospholipid-binding domains into a variety of signaling complexes often at the plasma membrane ((Vanhaesebroeck et al., Annu. Rev. Biochem 70:535 (2001); Katso et al., Annu. Rev. Cell Dev. Biol. 17:615 (2001)). Of the two Class 1 PI3Ks, Class 1A PI3Ks are heterodimers composed of a catalytic p110 subunit (α, β, δ isoforms) constitutively associated with a regulatory subunit that can be p85α, p55α, p50α, p85β or p55γ. The Class 1B sub-class has one family member, a heterodimer composed of a catalytic p110γ subunit associated with one of two regulatory subunits, p101 or p84 (Fruman et al., Annu Rev. Biochem. 67:481 (1998); Suire et al., Curr. Biol. 15:566 (2005)). The modular domains of the p85/55/50 subunits include Src Homology (SH2) domains that bind phosphotyrosine residues in a specific sequence context on activated receptor and cytoplasmic tyrosine kinases, resulting in activation and localization of Class 1A PI3Ks. Class 1B PI3K is activated directly by G protein-coupled receptors that bind a diverse repertoire of peptide and non-peptide ligands (Stephens et al., Cell 89:105 (1997)); Katso et al., Annu. Rev. Cell Dev. Biol. 17:615-675 (2001)). Consequently, the resultant phospholipid products of class I PI3K link upstream receptors with downstream cellular activities including proliferation, survival, chemotaxis, cellular trafficking, motility, metabolism, inflammatory and allergic responses, transcription and translation (Cantley et al., Cell 64:281 (1991); Escobedo and Williams, Nature 335:85 (1988); Fantl et al., Cell 69:413 (1992)).
In many cases, PIP2 and PIP3 recruit Akt, the product of the human homologue of the viral oncogene v-Akt, to the plasma membrane where it acts as a nodal point for many intracellular signaling pathways important for growth and survival (Fantl et al., Cell 69:413-423 (1992); Bader et al., Nature Rev. Cancer 5:921 (2005); Vivanco and Sawyer, Nature Rev. Cancer 2:489 (2002)). Aberrant regulation of PI3K, which often increases survival through Akt activation, is one of the most prevalent events in human cancer and has been shown to occur at multiple levels. In a variety of tumors, the genes for the p110α isoform, PIK3CA, and for Akt are amplified and increased protein expression of their gene products has been demonstrated in several human cancers. Further, somatic missense mutations in PIK3CA that activate downstream signaling pathways have been described at significant frequencies in a wide diversity of human cancers (Kang at el., Proc. Natl. Acad. Sci. USA 102:802 (2005); Samuels et al., Science 304:554 (2004); Samuels et al., Cancer Cell 7:561-573 (2005)).
Further, insulin-like growth factor-1 receptor (IGF-1R), a transmembrane tyrosine kinase, is widely expressed on normal tissues. The receptor is activated by binding of the natural ligands IGF-1 and IGF-2 and leads to activation of the PI3K/AKT pathway. Upon binding of a growth factor to a receptor tyrosine kinase, PI3K binds to the intracellular domain of the receptor tyrosine kinase. This interaction between receptor tyrosine kinase and PI3K occurs either directly or via adaptor molecules such as insulin receptor substrate 1 (IRS-1) leading to the activation of the lipid kinase activity. Upon activation, PI3K generates PIP3, a lipid “second messenger”, which in turn activates AKT (PKB), a serine/threonine kinase that is probably the best understood downstream effector of PI3K. The PI3K signaling is negatively regulated by action of dual specificity protein phosphatases/3-PI phosphatases, namely the tumor suppressor PTEN.
Activation of the PI3K/AKT pathway associated with increased IGF-1R signaling is known to occur in various cancer types, such as breast cancer, ovarian cancer, pancreatic carcinoma, colorectal cancer and melanoma. IGF-1R is often found to be overexpressed by cancer cell lines and human cancers, and many cancer cell lines are mitogenically responsive to physiological concentrations of IGFs. IGF-1R overexpression, however, in contrast to other receptor tyrosine kinase receptors, does not appear to be associated with gene amplification or gene mutation. IGF-1R is found to establish resistance to epidermal growth factor receptor (EGFR) inhibitors in EGFR amplified tumors by loss of insulin-growth factor binding protein expression.
Many cancers, particularly those carrying EGFR amplification, IGF1R overexpression, PIK3CA amplification, and/or PIK3CA mutation are amenable to treatment with epidermal growth factor receptor (EGFR) inhibitors, IGF1R inhibitors, aromatase inhibitors, and/or chemotherapy. However, in many cases the cancers acquire resistance to these chosen therapeutic and ultimately become refractory to treatment.
In spite of numerous treatment options for cancer patients, there remains a need for effective and safe therapeutic agents and a need for their preferential use in combination therapy. In particular, there is a need in the art for novel methods of treating cancers, particularly those carrying EGFR amplification, EGFR amplification and PI3K signaling, IGF1R overexpression, PIK3CA amplification, and/or PIK3CA mutation cancers, especially those cancers that have been resistant and/or refractive to current therapies.